Translating evidence into global impact: lessons for HIV research and policy development from the AMBITION trial
Authors: Joseph N Jarvis, Roger Chou, Thomas S Harrison, David S Lawrence, Charles Muthoga, Kennedy Mupeli, David B Meya, Henry C Mwandumba, Cecilia Kanyama, Graeme Meintjes, Tshepo B Leeme, Chiratidzo E Ndhlovu, Pauline Beattie, Omar Sued, Carmen Pérez Casas, Michael Makanga, Nathan Ford
Journal: The Lancet Global Health (2023)

Translating evidence from clinical trials to routine care can take many years, particularly in low-income and middle-income countries, delaying access to life-saving or life-changing treatments. As few as one in five evidence-based health interventions are incorporated into routine use, and the average time lag between evidence availability and practice change is up to 17 years.1Morris ZS Wooding S Grant J The answer is 17 years, what is the question: understanding time lags in translational research.J R Soc Med. 2011; 104: 510-520Crossref PubMed Scopus (1670) Google Scholar The results of the AMBITION trial, which provided evidence supporting a simpler, safer treatment for HIV-associated cryptococcal meningitis, were published in full on March 24, 2022.2Jarvis JN Lawrence DS Meya DB et al.Single-dose liposomal amphotericin b treatment for cryptococcal meningitis.N Engl J Med. 2022; 386: 1109-1120Crossref PubMed Scopus (75) Google Scholar A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022.3WHOGuidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV.https://www.who.int/publications/i/item/9789240052178Date: June 27, 2022Date accessed: September 22, 2023Google Scholar The rapid development of WHO guidelines facilitated incorporation of the new regimen into national guidelines in the African countries where the trial was done, and more broadly in other countries in Africa, Asia, Europe, and Latin America, with patients receiving the new treatment as part of routine care within 3 months. In this Comment, we highlight some key lessons to accelerate knowledge translation. 40 years ago, Yusuf and colleagues stated that a good clinical trial should ask an important question and answer it reliably.4Yusuf S Collins R Peto R Why do we need some large, simple randomized trials?.Stat Med. 1984; 3: 409-422Crossref PubMed Scopus (599) Google Scholar Cryptococcal meningitis is a leading cause of HIV-associated mortality.5Rajasingham R Govender NP Jordan A et al.The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.Lancet Infect Dis. 2022; 22: 1748-1755Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar Until recently, the standard of care required 7–14 days of daily intravenous infusions of amphotericin B, causing significant toxicities and limiting safe use in most resource-constrained hospitals, with acute mortality rates of 40% or more.6Tenforde MW Shapiro AE Rouse B et al.Treatment for HIV-associated cryptococcal meningitis.Cochrane Database Syst Rev. 2018; 7CD005647PubMed Google Scholar Guideline development relies on a comprehensive evidence assessment, appraised by a diverse, representative group of experts, providing an opportunity to identify crucial research gaps. The WHO cryptococcal disease guidelines from 2018 noted that simple treatments for cryptococcal meningitis suitable for low-resource settings were urgently needed.7WHOGuidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.https://www.who.int/publications/i/item/9789241550277Date: March 1, 2018Date accessed: September 22, 2023Google Scholar The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis.2Jarvis JN Lawrence DS Meya DB et al.Single-dose liposomal amphotericin b treatment for cryptococcal meningitis.N Engl J Med. 2022; 386: 1109-1120Crossref PubMed Scopus (75) Google Scholar The trial was sufficiently powered to evaluate safety and efficacy, and was done across five sub-Saharan African countries, enabling assessment of consistency of effects across different settings. The identification of the key questions was further supported by longstanding collaborations, including many African clinical researchers working in diverse health-care settings. Guideline development at WHO follows the Grading of Recommendations, Assessment, Development, and Evaluation process, with explicit consideration of four domains: certainty of the evidence, values and preferences, balance of benefits and harms, and resource implications. Other factors such as equity and human rights, acceptability, and feasibility are also considered.8WHOWHO handbook for guideline development, 2nd edition.https://www.who.int/groups/guidelines-review-committeeDate: Dec 18, 2014Date accessed: September 22, 2023Google Scholar Typically, trials focus only on safety and efficacy. To consider the full range of evidence-to-decision domains, guideline developers are often required to consider indirect evidence, rely on expert judgement, or await the findings of other relevant studies (such as qualitative surveys to assess acceptability), potentially adding months or years to guideline development. The AMBITION trial took these broader considerations into account from the outset through nested cost-effectiveness,9Lawrence DS Muthoga C Meya DB et al.Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.Lancet Glob Health. 2022; 10: e1845-e1854Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar acceptability, and feasibility10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar studies (table). Funding to perform these analyses within the main trial was crucial to ensuring that guideline developers were provided with all the information required to formulate a recommendation.TableEvidence-to-decision table for the treatment of cryptococcal meningitisSource of informationJudgementPriority of the problemPublished estimate of global disease burden5Rajasingham R Govender NP Jordan A et al.The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.Lancet Infect Dis. 2022; 22: 1748-1755Summary Full Text Full Text PDF PubMed Scopus (89) Google ScholarHigh priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deathsBalance of benefits and harmsPhase 3 clinical endpoint trial (the AMBITION trial)2Jarvis JN Lawrence DS Meya DB et al.Single-dose liposomal amphotericin b treatment for cryptococcal meningitis.N Engl J Med. 2022; 386: 1109-1120Crossref PubMed Scopus (75) Google ScholarBenefits outweigh harms: non-inferior mortality; fewer adverse eventsAcceptability to key stakeholdersEthnographic study (the LEOPARD study)10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observationsHighly acceptable from the perspective of participants and providersFeasibility of implementationEthnographic study (the LEOPARD study)10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigatorsFeasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of careResource requirementsEconomic evaluation9Lawrence DS Muthoga C Meya DB et al.Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.Lancet Glob Health. 2022; 10: e1845-e1854Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar embedded within the phase 3 clinical trialCost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementationEffect on health equityEquity considerations provided during the guideline meetingImproves equityFor a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. Gathering information early to inform these recommendations is crucial to accelerating guideline development. Open table in a new tab For a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. Gathering information early to inform these recommendations is crucial to accelerating guideline development. Throughout the trial, investigators engaged stakeholders and policy makers, including ministries of health, global organisations, and the pharmaceutical industry. WHO technical staff kept in close contact with trial investigators to anticipate when trial results would be available, so that a guideline panel could be convened, with investigators sharing efficacy, costing, feasibility, and acceptability data before publication. Engaging communities affected by HIV-associated cryptococcal meningitis enriched trial development and conduct, and was essential in showing acceptability and feasibility10Lawrence DS Ssali A Moshashane N et al.The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: findings from a qualitative methods study of participants and researchers in Botswana and Uganda.PLoS Negl Trop Dis. 2022; 16e0010825Crossref PubMed Scopus (3) Google Scholar and helping to ensure that results were widely disseminated. Senior trial investigators contributed to national guideline-writing committees in countries where the trial was done, engagement with the Drugs for Neglected Diseases Initiative and generic drug manufactures has led to increased availability and reduced costs of the essential companion drug flucytosine, and work with Médecins Sans Frontières and other implementing partners facilitated access to and uptake of the novel treatment. Gilead supported the preliminary phase 2 studies, donated liposomal amphotericin B for the trial, and stated their commitment to preferential pricing following trial completion, although this remains to be fully honoured. Catalytic funding from Unitaid to the Clinton Health Access Initiative established initial access to the key commodities needed for roll-out of the new treatment in African markets, a crucial factor in rapid uptake and implementation of WHO guidelines. Extensive advocacy activities were done throughout the trial, highlighting the ongoing burden of disease and the need for new treatments,5Rajasingham R Govender NP Jordan A et al.The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.Lancet Infect Dis. 2022; 22: 1748-1755Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar leading to an increase in global flucytosine production by generic manufacturers, substantial cost reduction, and widespread uptake in several African countries; however, considerable challenges remain. Access to both liposomal amphotericin B and flucytosine is far from universal, and the cost of liposomal amphotericin B is excessively high in several countries where exclusive distribution contracts prevent access to Gilead's preferential pricing.11Burry J Perez Casas C Ford N Access to medicines for treating people with cryptococcal meningitis.Clin Infect Dis. 2023; 76: e773-e775Crossref PubMed Scopus (3) Google Scholar The AMBITION trial shows that a single large and well done trial can rapidly and credibly translate research evidence to international clinical practice. Research teams who reliably answer important questions, simultaneously generate all evidence for decision making, and work with diverse stakeholders to advocate for change are more likely to rapidly change policy and practice and improve human health. We would like to thank all investigators and participants in the AMBITION trial and associated substudies, community members, and the funders of the trial. The AMBITION trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (TRIA2015-1092), and the Wellcome Trust/Medical Research Council (MRC) UK/UKAID Joint Global Health Trials (MR/P006922/1). Additional funding was provided by the National Institute for Health Research (NIHR) through a Global Health Research Professorship (RP-2017-08-ST2-012, to JNJ) with aid from the UK Government to support global health research. JNJ is funded by the National Institute for Health and Care Research (NIHR) through a Global Health Research Professorship (RP-2017-08-ST2-012) using UK aid from the UK Government to support global health research and received grant payments from the NIHR and EDCTP to his institution. RC received consulting fees to serve as methodologist for the updated WHO guideline on cryptococcal meningitis. TSH and DSL received support for the underlying AMBITION trial to institution from EDCTP, MRC, and Wellcome Trust, UK aid from the UK Government to support global health research, and provision of drug for the underlying AMBITION trial from Gilead. All other authors declare no competing interests. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The writing of this Comment was supported by a grant from the Bill & Melinda Gates Foundation. We are grateful to Susan L Norris and Rebekah Thomas for providing comments on an earlier draft.